Biswulfenioidins A–E, dioxygen-bridged abietane-type diterpenoid dimers with anti-Zika virus potential from Orthosiphon wulfenioides

Abstract

Five novel abietane-type diterpenoid dimers (ADDs), biswulfenioidins A–E (1–5), one known bisditerpenoid (6), and two possible precursors (7 and 8) were isolated from O. wulfenioides. Their structures were determined and characterized by X-ray diffraction, quantum chemical calculations, and extensive spectroscopic methods. Compounds 1–4 were unprecedented 6-O-12′ and 7-O-11′ angular fused dioxygen-bridged ADDs, while 5 and 6 were rare 6-O-7′ and 7-O-6′ parallel fused. Putative biosynthetic pathways of 1–6 were proposed. Interestingly, possible precursors 7 and 8 showed high cytotoxic effects, while dimerized diterpenoids 1–6 exhibited negligible cytotoxicity against Vero cells. Compounds 5 and 6 showed potent activity against Zika virus (ZIKV) superior to the positive drug ribavirin. Western blot and immunofluorescence experiments exhibited that 5 interfered with the replication of the ZIKV by inhibiting the expression of the ZIKV envelope (E) and NS5 protein.